Process of making dosage units by wet granulation

ABSTRACT

The invention relates to a process of making pharmaceutical dosage units comprising at least desogestrel or Org 30659 (17α-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one), present in an amount of about 0.005 to 1.0 percent by weight of each pharmaceutical dosage unit, characterized in that the steroidal agent, and when required pharmaceutically acceptable excipients, are mixed with water and granulated.

The invention relates to a process of making dosage units comprising atleast desogestrel or Org 30659(17α-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one) presentin an amount of about 0.005 to 1.0 percent by weight of eachpharmaceutical dosage unit.

Methods for making tablets and other solid or dry pharmaceuticalpreparations are well-known. For example in the standard Englishlanguage text Gennaro et al., Remington's Pharmaceutical Sciences, (18thed., Mack Publishing Company, 1990, see especially Part 8:Pharmaceutical Preparations and Their Manufacture), methods of makingtablets, capsules and pills and their respective components aredescribed.

Three methods of making tablets include the wet-granulation,dry-granulation, and direct compression methods. Wet-granulation methodsinvolve weighing out ingredients (including a solvent), mixing theingredients, granulating them, screening them damp, drying them, dryscreening, lubrication, and compressing the resultant admixture intotablets. Such procedures result in tablets having at least adequatetablet homogeneity. Wet-granulation methods may have a disadvantage whencertain solvents, which may not be desired in view of environmental andsafety concerns, are used.

An additional problem occurs in providing optimal tablet homogeneitywhen used with certain very potent medicinal compounds. For example,compounds such as certain extremely potent steroids require only verylow doses of the compound per tablet (e.g. <1.0 milligrams (mg)/100 mgtablet) and do not always distribute entirely evenly throughout atableting mixture possibly resulting in some tablets having relativelyhigh amounts of steroid (i.e. "superpotent tablets"), while others havevery low amounts of steroid or possibly none at all.

Very few solutions for these problems are offered, among which a dry-mixprocedure as disclosed in European patent application 503,521.

The present invention offers a novel solution for obtaining tabletscomprising low dosage of the micronised or finely milled steroidalprogestogens desogestrel or Org 30659 with excellent content uniformity,by using a wet-granulation technique, in which the progestogen, andoptionally pharmaceutically acceptable excipients, are mixed with waterand granulated. The granulate obtained may optionally be mixed withpharmaceutically acceptable auxiliaries, and compressed into tablets.

The method is very suitable for tablets comprising the low dosagesteroidal progestogens desogestrel or Org 30569, which are present in anamount of about 0.005 to 1.0, and preferably of about 0.01 to 0.5percent by weight of each pharmaceutical dosage unit. Under desogestrelis also to understand its active metabolite 3-keto-desogestrel.

The progestogens desogestrel and Org 30659 can be admixed with estrogensselected from ethinyl estradiol (EE), estradiol, and mestranol. Usuallymixtures of progestogens and estrogens are used. Most preferred aretablets comprising desogestrel and ethinyl estradiol.

Since tablets containing desogestrel (and also tablets containing Org30659) are known to be unstable towards moisture, many attempts are doneto exclude water in the manufacture process, for instance by using adry-granulating method, or by using water-free organic solvents inwet-granulating methods. The marketed product (Marvelon®), for instance,is packed in a water impermeable sachet to prevent contact between thetablet and surrounding. Most remarkably it has now been found that theprocess of this invention, comprising granulation in an aqueous medium,provides a granulate of desogestrel or Org 30659 and ethinyl estradiol,from which tablets can be prepared which are much more stable towardsmoisture, than the previously aqueous-free prepared tablets.

Wet granulation distinguishes from dry granulation in that water ororganic solvents are applied in wet granulation to produce agglomerationor granules.

The most widely used granulation methods in the pharmaceutical industryare the fluidized bed granulation and the wet-massing method in which aliquid is added to a powder or granulate in a vessel equipped with anytype of agitation that will provide granules or agglomerates. Variousoperations can be recognised in the wet (massing) granulation, includingmilling of drugs and excipients, mixing of milled powders, preparationof binder solution, mixing the binder solution with the powder mixtureto form the wet mass, coarse screening of wet mass, drying moistgranules, screening dry granules, mixing the screened granules withlubricant and disintegrant, and finally filling the granulate intocapsules or compressing the granulate to tablets. It is obvious that,depending on the selected excipients and the size of the batch and theselected equipment, some of the operations can be combined or are notrequired or particular operations can be included. General methods ofpreparing granules are for instance described in Pharmaceutical DosageForms: Tablets (Volume I). Ed. H. A. Lieberman, L. Lachman, J. B.Schwartz (1989), Marcel Dekker Inc. New York and Basel pp. 131-190.

Advantages of wet granulation include improvement of the cohesivenessand compressibility of powders, a good distribution and uniform contentof micronised or finely milled low-dosage drugs, reduction of a greatdeal of dust and airborne contamination, prevention of segregation ofcomponents.

Small-scale production can be achieved by mixing and wetting the mass inmortars or stainless steel bowls, whereas for larger quantitiestwin-shell blenders, double-cone blenders, planetary mixers, rotarygranulators, high shear mixers and fluid-bed granulation equipment canbe applied. General mixing methods are disclosed in PharmaceuticalDosage Forms (Volume 2). Ed. H. A. Lieberman, L. Lachman, J. B. Schwartz(1990), Marcel Dekker Inc. New York and Basel pp. 1-71. The dryexcipients and the micronised or finely milled active ingredients aremixed in a suitable mixer, preferably a mixer in which both mixing andgranulating can be performed, for instance a Gral high sheer mixer,after which an aqueous binder solution is added. Another preferredmethod is to suspending the active ingredients into the aqueous bindersolution, which suspension is added to the dry mixture of excipients andgranulated.

Granulates and tablets prepared by wet-granulation consist of severalinert materials that can be found in conventional solid oral dosageforms in general. The ingredients can be classified in excipients whichhelp to impart satisfactory processing and compression characteristicsto the formulation like diluents, binders, glidants and lubricants andin excipients to give the desirable physical characteristics to thefinished tablet like disintegrants and colors. If required the tabletscan be provided with a film coat, for instance as disclosed inPharmaceutical Dosage Forms (Volume 3). Ed. H. A. Lieberman, L. Lachman,J. B. Schwartz (1990), Marcel Dekker Inc. New York and Basel pp. 93-125.

Diluents (fillers) or bulking agents usually make up the major portionof the tablet. The group of most commonly used diluents include thewater insoluble calcium phosphates (di- and tribasic), calcium sulfatedihydrate, calcium carbonate, starch, modified starches andmicrocrystalline cellulose and the water soluble lactose, sucrose,dextrose, mannitol and sorbitol.

The substances that bind powders together and provide cohesiveness tothe tablet formulation are binding agents or adhesives. Binders can beadded dry and blended with the diluents and the drug. In this casebinders are activated by addition of water or other solvents. In othermanufacturing procedures, the adhesives are dissolved or slurried in aliquid and, in this form, added to the mixed powders. Conventionalbinders include gelatin, water soluble modified starch, and sugars assucrose, glucose, dextrose, molasses and lactose. Natural and syntheticgums which have been used include tragacanth, magnesium aluminiumsilicate, acacia, ammonium calcium alginate, sodium alginate,carboxymethylcellulose, hydroxypropylcellulose, methylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycoland clays like Veegum. Depending on for example the solubility of thebinders in the various liquids, the binder can be added to the powdermix as a solution in water, a water-solvent mixture and in a organicsolvent.

Materials to improve the flow characteristics are referred to asglidants. As an example, silicon dioxide, magnesium lauryl sulfate,magnesium aluminium silicate, magnesium oxide, talc or clays can beincorporated into the formulation to reduce interparticulate frictionand to eliminate the problems associated with the flow of materials fromlarger to smaller apertures in the tablet presses.

Before filling capsules or sachets, or compressing tablets, lubricantsare mostly added to prevent friction and wear during processing. Some ofthe lubricants also demonstrate anti-adherent properties that can berelevant in case of sticking of tablet granulations to the faces of thepunches and the die walls. Examples of the group of lubricants are themetallic stearates (magnesium stearate), talcum, stearic acid, sodiumstearyl fumarate, hydrogenated vegetable oil, high melting point waxes,and corn starch.

A component incorporated into the tablets to help the tablet to break upand dissolve to release the active component is the disintegrant. Thetotal amount of disintegrant can be added to the granulation just priorto compression, can be added to the total mass of powdered materialsbefore the wet granulation process takes place or can be simply dividedinto one portion added before wet granulation and one portion added dryto the granulates. Examples of the group of disintegrants that can beapplied are starch (Starch 1500), microcrystalline cellulose (Avicel PH101 and Avicel PH 102), purified wood cellulose, alginic acid, sodiumstarch glycolate, guar gum, cross carmellose sodium, crosslinkedpolyvinylpyrrolidone and ion exchange resins.

The tablets obtained by the process of this invention are free fromorganic solvents, and comprise a progestogen selected from desogestreland Org 30659, present in an amount of about 0.005 to 1.0 percent byweight of each pharmaceutical dosage unit, a small amount being lessthan 20% (e.g. 0.5-20%), and preferably less than 10% by weight ofwater, and optionally an estrogen. Preferably the progestogen isdesogestrel and the estrogen is ethinyl estradiol. The amount of watercan vary and depends from the drying conditions applied. The tablets,however, always possess trace amounts of water, usually less than 10% byweight, and preferably about 0.5 to 10% by weight.

The invention is further illustrated by the following examples.

EXAMPLE I

The active ingredients were processed to a homogeneous granulationcomprising (per tablet):

    ______________________________________    desogestrel (micronised)      150 μg    EE (micronised)                30 μg    hydroxypropylcellulose       1.95 mg    corn starch                  6.50 mg    colloidal silicon dioxide    0.98 mg    magnesium stearate           0.33 mg    lactose         to             65 mg    ______________________________________

For a 1 kg batch a Gral 10 high shear mixer was filled with lactose 200Mand corn starch. After mixing for 1 min a dispersion of desogestrel andEE (ethinyl estradiol) in an aqueous granulation solution ofhydroxypropylcellulose (125 ml) was added quantitatively to the mass.Then 25 ml of water was used to rinse the beaker and subsequently addedto the mixture. The mixture was granulated with the Gral 10 for 2.5minutes. The obtained wetted mass was dried for 4 h in a Marius vacuumcabinet under diminished pressure at 40° C. After drying and screeningthrough a 710 μm sieve with an Erweka apparatus the granulate wasadmixed with colloidal silicon dioxide and magnesium stearate. Thegranulate was compressed to tablets.

EXAMPLE II

A granulate with the composition in Example I was manufactured. Thegranulation was performed with ethanol instead of water in the bindersolution.

EXAMPLE III

Tablets from Example I and Example II were subjected to storage at 40°C. for two months at relative humidities (RH) of 10 and 95%respectively. The decomposition of desogestrel was calculated.

    ______________________________________                   Decomposition (%)                   10% RH 95% RH    ______________________________________    Tablets Example II                     1        4    Tablets Example I                     0        1    ______________________________________

Tablets prepared without aqueous binder solution show susceptibility tohumidity upon storage (Example II), whereas tablets prepared with anaqueous binder solution show less susceptibility to humidity and animproved stability (Example I).

EXAMPLE IV

The active ingredients were processed to a homogeneous granulationcomprising:

    ______________________________________    Org 30659 (finely milled)                              60 μg    hydroxypropylcellulose  1.95 mg    corn starch             6.50 mg    magnesium stearate      0.325 mg    lactose                56.165 mg    ______________________________________

For a 1 kg batch a Gral 10 high shear mixer was filled with lactose 200Mand corn starch. After mixing for 1 min a dispersion of Org 30659(17α-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one) in anaqueous granulation solution of hydroxypropylcellulose (125 ml) wasadded quantitatively to the mass. Then 25 ml of water was used to rinsethe beaker and subsequently added to the mixture. The mixture wasgranulated with the Gral 10 for 2.5 minutes. The obtained wetted masswas dried for 4 h in a Marius vacuum cabinet under diminished pressureat 40° C. After drying and screening through a 710 μm sieve with anErweka apparatus the granulate was admixed with magnesium stearate. Thegranulate was compressed to tablets.

EXAMPLE V

A granulate with the composition in Example IV was manufactured. Thegranulation was performed with ethanol instead of water in the bindersolution.

EXAMPLE VI

Tablets from Example IV and Example V were subjected to storage at 30°C. for one month at relative humidities (RH) of 10 and 95% respectivelyin open glass containers. The decomposition of Org 30659 was calculated.

    ______________________________________                    Decomposition (%)                    10% RH 95% RH    ______________________________________    Tablets Example V 0        6    Tablets Example IV                      0        0    ______________________________________

Tablets prepared without aqueous binder solution show susceptibility tohumidity upon storage (Example V), whereas tablets prepared with anaqueous binder solution show less susceptibility to humidity and animproved stability (Example IV).

EXAMPLE VII

The active ingredients were processed to a homogeneous granulationcomprising (per tablet):

    ______________________________________    desogestrel (micronised)      150 μg    EE (micronised)                30 μg    hydroxypropylcellulose       1.95 mg    corn starch                  6.50 mg    colloidal silicon dioxide    0.98 mg    magnesium stearate           0.33 mg    lactose         to             65 mg    ______________________________________

For a 1 kg batch a Gral 10 high shear mixer was filled with lactose200M, corn starch, desogestrel and EE (ethinyl estradiol). After mixingfor 1 min an aqueous granulation solution of hydroxypropylcellulose (125ml) was added quantitatively to the mass. Then 25 ml of water was usedto rinse the beaker and subsequently added to the mixture. The mixturewas granulated with the Gral 10 for 2.5 minutes.

The obtained wetted mass was dried for 4 h in a Marius vacuum cabinetunder diminished pressure at 40° C. After drying and screening through a710 μm sieve with an Erweka apparatus the granulate was admixed withcolloidal silicon dioxide and magnesium stearate. The granulate wascompressed to tablets.

EXAMPLE VIII

The active ingredients were processed to a homogeneous granulationcomprising:

    ______________________________________    Org 30659 (finely milled)      60 μg    polyvinylpyrrolidone          1.95 mg    corn starch                   6.50 mg    magnesium stearate           0.325 mg    lactose          to            65 mg    ______________________________________

and granulated and compresses into tablets according to the method ofExample IV.

EXAMPLE IX (COMPARISON EXAMPLE)

A granulate having the composition of Example VIII was manufacturedusing acetone instead of water. The tablets obtained therefrom werestored for 12 months at 75% relative humidity at 30° C. and 40° C. inopen glass containers. The tablets of Example VIII were stored under thesame conditions and the content in percentage of the initial content atzero time was calculated:

    ______________________________________                     30° C.                           40° C.    ______________________________________    Tablets Example VIII                       94.4%   73.6%    Tablets Example IX 64.1%   44.5%    ______________________________________

EXAMPLE XI

    ______________________________________    Tablets were prepared comprising:    ______________________________________    Org 30569 (micronised)         7.5 μg    estradiol                        2 mg    hydroxypropylcellulose         1.95 mg    corn starch                     30%    colloidal silicon dioxide      0.98 mg    magnesium stearate            0.325 mg    lactose            to           65 mg    ______________________________________

Granulation was performed according to Example IV using 280 ml ofgranulation liquid to obtain granulates. Tablets were compressed on arotary press.

We claim:
 1. A process of making pharmaceutical dosage units units comprising at least one steroidal progestogen selected from the group consisting of desogestrel and 17α-17-hydroxy-11-methylene-19-norpregna-4.15-dien-20-yn-3-one, present in an amount of about 0.005 to 1.0 percent by weight of each pharmaceutical dosage unit, comprising mixing the progestogen with pharmaceutically acceptable excipients and water and granulating the mixture.
 2. The process according to claim 1, wherein the resulting granulate is compressed into tablets.
 3. The process according to claim 1, wherein the progestogen is present in an amount of about 0.01 to 0.5 percent by weight of each pharmaceutical dosage unit.
 4. The process according to claim 1, wherein the progestogen is admixed with an estrogen.
 5. The process according to claim 1, wherein the progestogen is desogestrel.
 6. A tablet free from organic solvents, comprising a progestogen selected from desogestrel and Org 30659, present in an amount of about 0.005 to 1.0 percent by weight of each pharmaceutical dosage unit, and less than 20% by weight of water.
 7. The tablet of claim 6, wherein the progestogen is desogestrel.
 8. The process of claim 1, wherein the resulting granulate is compressed into tablets.
 9. The process of claim 1, wherein the amount of progestogen is about 0.01 to 0.5 percent by weight of each pharmaceutical dosage unit.
 10. The process of claim 9, wherein the progestogen is admixed with an estrogen.
 11. The process of claim 9, wherein the progestogen is desogestrel.
 12. The process of claim 10, wherein the estrogen is ethinyl estradiol.
 13. The process of claim 4, wherein the estrogen is ethinyl estradiol.
 14. The table of claim 6, further comprising an estrogen.
 15. The tablet of claim 14, wherein the estrogen is ethinyl estradiol. 